TME-activated MXene nanoheterojunctions engineer cancer cells through phototherapy and metabolic interference for enhanced cuproptosis and immunotherapy

The nanoheterojunction (NbCuF@MR) enables tumor-specific copper delivery. • Its TME-responsive design minimizes systemic toxicity and off-target effects. • The cascade amplifies oxidative stress to activate robust ICD. • Cuproptosis–immunomodulation–metabolic interference reprograms the TME. • It enhances immune infiltration, converting “cold” tumors into “hot” ones. Cuproptosis, an emerging copper-dependent programmed cell death, offers a promising strategy for cancer therapy. However, its clinical translation is hindered by non-targeted Cu release, causing systemic toxicity and limited efficacy. To overcome this, we developed a folate-targeted nanoheterojunction photosensitizer, NbCuF@MR, for tumor-specific copper delivery. This system responds to the tumor microenvironment to release active components, leading to mitochondrial copper accumulation, aggregation of lipoylated dihydrolipoamide S -acetyltransferase (DLAT), and induction of cuproptosis. Under 808 nm laser irradiation, Nb 2 C generates mild phototherapy effects that combine to enhance cuproptosis while producing ROS and O 2 . Furthermore, this cascade reactions promotes immunogenic cell death (ICD). Together with loaded R848 and MTX, the system reprograms the immunosuppressive tumor microenvironment through metabolic modulation and amplified cuproptosis, activating a robust antitumor immune response. This stimulates M1 macrophage polarization, DC maturation, and cytotoxic T-cell infiltration, effectively inhibiting both local and distant tumor growth and metastasis. In conclusion, this work offers an innovative strategy leveraging metabolic interference and enhanced cuproptosis to activate potent antitumor immunity. Download: Download high-res image (159KB) Download: Download full-size image